SG193491A1 - Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor - Google Patents
Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor Download PDFInfo
- Publication number
- SG193491A1 SG193491A1 SG2013069695A SG2013069695A SG193491A1 SG 193491 A1 SG193491 A1 SG 193491A1 SG 2013069695 A SG2013069695 A SG 2013069695A SG 2013069695 A SG2013069695 A SG 2013069695A SG 193491 A1 SG193491 A1 SG 193491A1
- Authority
- SG
- Singapore
- Prior art keywords
- omega
- coating layer
- complex composition
- fatty acid
- soft capsule
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 62
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title abstract description 22
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title abstract description 16
- 235000020660 omega-3 fatty acid Nutrition 0.000 title description 20
- 229940012843 omega-3 fatty acid Drugs 0.000 title description 20
- -1 omega-3 fatty acid ester Chemical class 0.000 title description 13
- 229940122601 Esterase inhibitor Drugs 0.000 title 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical class C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims abstract description 31
- 239000007901 soft capsule Substances 0.000 claims description 60
- 238000000576 coating method Methods 0.000 claims description 56
- 239000011247 coating layer Substances 0.000 claims description 54
- 239000011248 coating agent Substances 0.000 claims description 53
- 229960000672 rosuvastatin Drugs 0.000 claims description 28
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 28
- 230000002209 hydrophobic effect Effects 0.000 claims description 25
- 239000000463 material Substances 0.000 claims description 25
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 15
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000001856 Ethyl cellulose Substances 0.000 claims description 12
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 12
- 229920001249 ethyl cellulose Polymers 0.000 claims description 12
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 12
- 229920000578 graft copolymer Polymers 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 6
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims description 5
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims description 5
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims description 5
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000020669 docosahexaenoic acid Nutrition 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- 229940090949 docosahexaenoic acid Drugs 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 229920002126 Acrylic acid copolymer Polymers 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims description 2
- 239000011118 polyvinyl acetate Substances 0.000 claims description 2
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 17
- 238000003860 storage Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 9
- 210000002966 serum Anatomy 0.000 abstract description 8
- 230000003111 delayed effect Effects 0.000 abstract description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- 230000004888 barrier function Effects 0.000 description 11
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 10
- 239000002775 capsule Substances 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 150000003626 triacylglycerols Chemical class 0.000 description 7
- 102000007330 LDL Lipoproteins Human genes 0.000 description 6
- 108010007622 LDL Lipoproteins Proteins 0.000 description 6
- 102000015779 HDL Lipoproteins Human genes 0.000 description 5
- 108010010234 HDL Lipoproteins Proteins 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical class [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 5
- 239000008118 PEG 6000 Substances 0.000 description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000006014 omega-3 oil Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000013557 residual solvent Substances 0.000 description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- WFMVQPURDPTNBD-NSHDSACASA-N (3,3-difluoroazetidin-1-yl)-[(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone Chemical compound FC1(F)CN(C1)C(=O)C1=NN2[C@@H](CCC2=N1)C1=CC=CC=C1 WFMVQPURDPTNBD-NSHDSACASA-N 0.000 description 2
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 2
- 208000032928 Dyslipidaemia Diseases 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 238000008214 LDL Cholesterol Methods 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical class [Na+].COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 229940066901 crestor Drugs 0.000 description 2
- 239000010696 ester oil Substances 0.000 description 2
- DTMGIJFHGGCSLO-FIAQIACWSA-N ethyl (4z,7z,10z,13z,16z,19z)-docosa-4,7,10,13,16,19-hexaenoate;ethyl (5z,8z,11z,14z,17z)-icosa-5,8,11,14,17-pentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC.CCOC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC DTMGIJFHGGCSLO-FIAQIACWSA-N 0.000 description 2
- 229940013317 fish oils Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000012812 general test Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 2
- VWBQYTRBTXKKOG-IYNICTALSA-M pravastatin sodium Chemical compound [Na+].C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 VWBQYTRBTXKKOG-IYNICTALSA-M 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 1
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical class CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 description 1
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 229920000064 Ethyl eicosapentaenoic acid Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 229940019700 blood coagulation factors Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- ITNKVODZACVXDS-YNUSHXQLSA-N ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate Chemical compound CCOC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC ITNKVODZACVXDS-YNUSHXQLSA-N 0.000 description 1
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940095570 lescol Drugs 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229940002661 lipitor Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 229940099246 mevacor Drugs 0.000 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 230000020971 positive regulation of blood coagulation Effects 0.000 description 1
- 229940089484 pravachol Drugs 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004796 rosuvastatin calcium Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
An oral complex composition comprising omega-3 fatty acid esters and HMG-CoA reductase inhibitor, can effectively raise serum HDL level while reducing serum LDL and TG levels and can be used to treat hyperlipidemia owing to its good drug dissolution rate and storage stability with showing no delayed release behavior even after 6 months of accelerated storage.
Description
ORAL COMPLEX COMPOSITION COMPRISING OMEGA-3 FATTY
ACID ESTER AND HMG-COA REDUCTASE INHIBITOR
The present invention relates to an oral complex composition comprising omega-3 fatty acid esters and a HMG-CoA reductase inhibitor.
Marine oils, also commonly referred to as fish oils, are the main sources of omega-3 fatty acids, i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which modulate lipid metabolism. Omega-3 fatty acids can, with no adverse side effects, increase serum high-density lipoprotein (HDL) cholesterol while reducing serum triglycerides (TG), systolic and diastolic blood pressure, the heart rate, and the activation of blood coagulation factor VII-phospholipids complex.
Currently available omega-3 fatty acids drugs are omega-3 fatty acid ethyl esters (hereinafter, referred as "omega-3 fatty acid esters"), an ethyl-esterified concentration of omega-3 fatty acids, i.e. polyunsaturated fatty acids from DHA and
EPA-containing fish oils, and is sold under the trademark OMACOR® . Such omega-3 fatty acid esters are generally formulated into a capsule form such as gelatin capsules, as disclosed in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594. :
Besides natural fermentation products, mevastatin and lovastatin (MEVACOR®; see U.S. Patent No. 4,231,938), different types of synthesized and semisynthesized HMG-CoA reductase inhibitors are exist including simvastatin (ZOCOR®; see U.S. Patent No. 4,444,784), pravastatin sodium salt (PRAVACHOL®; see U.S. Patent No. 4,346,227), fluvastatin sodium salt (LESCOL®; see U.S. Patent No. 5,354,772), atorvastatin calcium salt (LIPITOR®; see U.S. Patent No. 5,273,995), cerivastatin sodium salt (also known as rivastatin;
see U.S. Patent No. 5,177,080), rosuvastatin calcium salt (CRESTOR; see KR.
Patent No. 105431) and pitavastatin calcium salt (LIVARO®; see KR Patent No. 101149). Such HMG-CoA reductase inhibitors contain 3-hydroxy lactones or corresponding ring opened dihydroxy acids, and are often referred to as "statins."
Statins were typically used for treatment to maintain cholesterol levels within the normal range. Statins can inhibit HMG-CoA reductase which regulates cholesterol synthesis thereby slowing down the production of cholesterol, or can reduce serum low-density lipoprotein (LDL) cholesterol by upregulating LDL receptors in the liver. Thus, the main function of the statins is diminishing LDL cholesterol.
Statins are known to reduce the risk of coronary heart disease (CHD) by one third, yet have limited effects on TG and serum HDL. oo
Patients with hypercholesterolemia and mixed dyslipidemia show high levels of LDL and TG. It is advantageous to use a pharmaceutical combination of omega-3 fatty acid esters and statins because it is applicable to treat high levels of both LDL and TG.
Therefore, development of a pharmaceutical combination of omega-3 fatty acid esters and statins may be useful for treating hyperlipidemia by raising serum
HDL while reducing LDL and TG levels. Hence, there has been much research on combined formulation of omega-3 fatty acid esters. For example, U.S. Patent
Publication No. 2007/0212411 disclosed combined formulations of OMACOR® by conducting, in sequence, polymer barrier coating, drug coating and top coating.
Examples of active pharmaceutical ingredients which can be used for the coatings include simvastatin, fenofibrate, pravastatin, propranolol, enalapril and prioglitazone.
Korean Patent Publication Nos. 2007-0038553, 2007-0108945 and 2009- 0086078 disclose pharmaceutical compositions of directly mixing omega-3 fatty acid esters with statins, however their drug stability cannot be guaranteed when directly mixed. Also, Korean Patent Publication Nos. 2007-0108945 and 2007- 0083715 relate to pharmaceutical compositions comprising statins or microcapsules thereif. . The compositions are formulated into a soft capsule form, mixed with omega-3 fatty acid oils which cause a delayed release of statin, so the dissolution rate of statin is much slower than that of commercially available statin drugs.
Currently, there is no complex composition drug comprising omega-3 fatty acid esters and HMG-CoA reductase inhibitor available having the same dissolution rate of statin as the commercial statin drugs. Therefore, there has been a need to develop a complex composition comprising omega-3 fatty acid esters and HMG-
CoA reductase inhibitors which is pharmaceutically stable; having the same dissolution rate and efficacy as commercial statin drugs; and does not show ‘a delayed release behavior even after long-term storage. :
Accordingly, it is an object of the present invention to provide an oral complex composition comprising omega-3 fatty acid esters and rosuvastatin or a pharmaceutically acceptable salt thereof, which exhibits an improved rosuvastatin releasing rate and does not show a delayed release behavior even after long-term storage.
It is another object of the present invention to provide a method for preparing the oral complex composition.
In accordance with one aspect of the present invention, there is provided an oral complex composition, which comprises: (a) a soft capsule core comprising omega-3 fatty acid esters; (b) a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material; and (c) a second coating layer deposited on the first coating layer, which comprises (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (ii) polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymer, or a mixture thereof.
In accordance with another object of the present invention, there is provided a method for preparing the oral complex composition, which comprises the steps of: (1) preparing a soft capsule core comprising omega-3 fatty acid esters; (2) forming a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material; and (3) forming a second coating layer on the first coating layer, which comprises (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (i) PVA, PVA-PEG graft copolymer, or a mixture thereof.
The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawings, which respectively show:
Fig. 1: the disintegration times of the capsules obtained in Comparative
Examples 1, 3 and Examples 1 to 7;
Fig. 2 : the disintegration times depending on the amount of ethyl cellulose in the capsules obtained in Comparative Example 3 and Examples 1 to 7;
Fig. 3 : the changes in water content of the capsules obtained in
Comparative Examples 1, 3 and Examples 1 to 7; and
Fig. 4 : the changes in dissolution rates of rosuvastatin in the capsules obtained in Comparative Examples 2, 4, 5 and Examples 8 to 12.
The inventive oral complex composition is characterized by comprising: (a) a soft capsule core comprising omega-3 fatty acid esters; (b) a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material; and (c) a second coating layer deposited on the first coating layer, which comprises the ingredients of (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (11) PVA, PVA-PEG graft copolymer, or a mixture thereof.
Hereinafter, the components contained in the oral complex composition of the present invention are described in detail. (a) Soft capsule core
The soft capsule core of the complex composition according to the present invention comprises omega-3 fatty acid esters as the first active pharmaceutical ingredient.
In one embodiment of the present invention, the omega-3 fatty acid esters may comprise ethyl esters of EPA and DHA in an amount of 80% by weight or more, preferably at least 40% by weight of EPA ethyl ester of and at least 34% by weight of DHA ethyl ester. Preferably, the omega-3 fatty acid esters may comprise ethyl ester of omega-3 fatty acid in an amount of 90% by weight or more.
The amount of the omega-3 fatty acid esters present in the soft capsule core may be 100 mg to 2,000 mg.
In a preferred embodiment of the present invention, the amount of the omega-3 fatty acid esters may be 70% to 95% by weight, based on the total weight of the soft capsule core, but not limited thereto.
Also, the soft capsule core can be prepared in a conventional manner for manufacturing soft capsules by using typical materials for soft capsules, e.g. gelatins. (b) First coating layer
In the oral complex composition of the present invention, the first coating layer comprises a hydrophobic coating material which encapsulates the soft capsule - core in order to prevent a change in water content inside the soft capsule core from affecting the dissolution rate of rosuvastatin-containing second coating layer and increase of related materials. When rosuvastatin is coated directly on the soft capsule core containing omega-3 fatty acid ester, then the water content of the capsule can affect the content of the rosuvastatin, reduce its dissolution rate and increase its related materials. In the present invention, however, the first coating layer comprising a hydrophobic coating material is employed in between the omega-3 fatty acid ester-containing soft capsule core and the rosuvastatin- containing second coating layer, minimizing the effect of water content as well as other potential risks.
Examples of the hydrophobic coating material may include cellulose acetate, polyvinyl acetate, ethyl cellulose, and (meth)acrylic acid copolymers, i.e. Eudragit®, preferably ethyl cellulose. The amount of the hydrophobic coating material used may be, based on the total amount of the first coating layer, 15% to 75% by weight, preferably 16% to 75% by weight, more preferably 16% to 72% by weight. If the amount of the hydrophobic coating material used is less than 15% by weight, the change in water content becomes greater, causing deterioration of storage stability by reducing rosuvastatin content and dissolution rate as well as increasing related materials.
The first coating layer may further comprise conventional coating materials such as hydroxypropyl methyl cellulose (HPMC) and hydroxylpropyl cellulose (HPC), which are generally used in the pharmaceutical field. In addition, the first coating layer may further comprise other pharmaceutically acceptable additives such as disintegrants, diluents, stabilizers, binders, and slip modifiers to the extent they do not adversely affect the disintegration rate of the capsule.
The first coating layer may be prepared by dissolving or dispersing the hydrophobic coating material in water, ethanol, or a mixture thereof, preferably in the mixed solvent, to obtain a coating solution and then applying the solution onto the surface of the soft capsule core.
The first coating layer may be coated on the soft capsule core in an amount of 2 parts by weight or more, preferably 4 to 10 parts by weight, based on 100 parts by weight of the soft capsule core. (¢) Second coating layer
In the oral complex composition of the present invention, the second coating layer comprises the ingredients of: (i) rosuvastatin or a pharmaceutically acceptable salt thereof, as the second active pharmaceutical ingredient, and (ii) PVA, PVA-PEG graft copolymer or a mixture thereof, as a coating material, which permits rapid release of rosuvastatin when dissolved and also prevents delayed release of rosuvastatin after being stored.
The second coating layer may be prepared by dissolving or dispersing said ingredients (i) and (ii) in water, ethanol or a mixture thereof, preferably in the mixed solvent, to obtain a coating solution, followed by applying the solution onto the surface of the first coating layer.
The amount of the ingredient (i) employed in the second coating layer may be
I mg to 50 mg, and the amount of the ingredient (ii) employed may be 25% to 85% by weight, preferably 25% to 80% by weight, based on the total amount of the second coating layer. :
The second coating layer may further comprise HPMC, polyvinylpyrrolidone (PVP), or a mixture thereof, and may also comprise other pharmaceutically acceptable additives such as alkaline stabilizers, if necessary.
The second coating layer may be coated on the first coating layer in an amount of 3 to 30 parts by weight, preferably 5 to 20 parts by weight, based on 100 parts by weight of the soft capsule core.
The present invention also provides a method for preparing the oral complex composition of the present invention, which comprises the steps of: (1) preparing a soft capsule core comprising omega-3 fatty acid esters; (2) forming a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material; and (3) forming a second coating layer on the first coating layer, which comprises the ingredients of (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (ii) PVA, PVA-PEG graft copolymer, or a mixture thereof.
Specifically, the method for preparing the oral complex composition of the present invention may comprise the following steps of: (1) preparing a soft capsule core containing omega-3 fatty acid esters in a conventional manner for manufacturing soft capsules; (2) forming a first coating layer encasing the soft capsule core by dissolving a hydrophobic coating material in a suitable solvent for barrier coating, e.g. in a mixture of ethanol and water, applying the coating solution onto the soft capsule core, and then drying the solution; and (3) forming a second coating layer on the first coating layer by dissolving the ingredients (i) and (ii) with alkaline stabilizers and/or other pharmaceutically acceptable additives in a suitable solvent, e.g. in a mixture of ethanol and water, applying the coating solution onto the surface of the first coating layer, and then drying the solution.
The complex composition of the present invention can be formulated into a capsule form, and can be administered orally.
The oral complex composition of the present invention can show a rosuvastatin or its pharmaceutically acceptable salt releasing rate of 80% or more in 0.05M citrate buffer within 30 min, preferably within 10 min; and no delayed release after storage duration of 6 months at 40°C under 75% relative humidity (RH). The above test results indicate good dissolution rate and storage stability and hence, it is possible to use in composite forms. : The oral complex composition of the present invention contains both omega-3 fatty acid esters and rosuvastatin, as active pharmaceutical ingredients, which can raise serum HDL level while reducing both LDL and TG levels. Thus, it can be used for effectively preventing or treating hypertriglyceridemia, hypercholesteremia, coronary arterial heart diseases (CAHD), dyslipidemia, and increased serum LDL cholesterol levels, and it can be used for preventing or treating cardiovascular diseases aswell.
The following Examples are provided to illustrate preferred embodiments of the present invention, and are not intended to limit the scope of the present invention.
Preparation of soft capsule core
Comparative Example 1: Soft capsule comprising omega-3 fatty acid ester
A soft capsule was prepared with 1,000 mg of omega-3 fatty acid ester oils by using a conventional method for manufacturing soft gelatin capsule.
Comparative Example 2: Soft capsule comprising omega-3 fatty acid esters and rosuvastatin
A soft capsule was prepared by repeating the procedures of Comparative
Example 1, except for employing a homogeneous mixture of 1,000 mg of omega-3 fatty acid ester oils and 10 mg of rosuvastatin.
First coating
Comparative Example 3: Omega-3 fatty acid ester soft capsule with conventional barrier coating
Co
In accordance with the ingredients described in Table 1, hydroxypropyl methyl cellulose (HPMC 2910, Shinetsu Co. Ltd., Japan), polyethylene glycol (PEG 6000,
Sanyo Chemical Industries, Ltd., Japan) and polyvinylpyrrolidone (PVP K-30, BASF
SE, Germany) were added to a mixture of ethanol and water, and then mixed to obtain a coating solution.
The coating solution was coated onto the surface of the soft capsule core prepared in Comparative Example 1 by using a coater (SFC-30, SEJONG Co., Ltd.), wherein the supply air temperature was 45°C and the product temperature was adjusted to 30°C. The product was dried for 30 minutes to remove residual solvent so that a soft capsule with a barrier coating was obtained.
Examples 1 to 7: Omega-3 fatty acid ester soft capsule with hydrophobic barrier coating
In accordance with the ingredients described in Table 1, a soft capsule with a hydrophobic barrier coating was prepared by repeating the procedures of Comparative
Example 3, except for adding ethyl cellulose (Dow Chemical Company, US) as a hydrophobic coating material.
The compositions of soft capsules and barrier coatings are summarized in
Table 1.
Table 1
Comp.| py 1 | Ex2 | Ex3 | Exd4 | Ex5 | Ex 6 | Ex.”
Ex. 3
Comp. | Comp. | Comp. | Comp. | Comp. | Comp. | Comp. | Comp.
Soft capsule core | my} | Ex.1 | Ex.1 | Ex.1 | Ex.1 | Bx.1 | Ex.1 | Bx.1
HPMC 2910
PEG 6000
PVP K-30 (% by weight) 10 10 10 10 10 10 10
Ethyl cellulose (% by weight) 0 sw mw wm we
Re (1040) | (1040) | (1040) | (1040) | (1040) | (1040) | (1040) | (1040)
PIII YIT | @0) | (440) | (440) | (440) | (440) | (440) | (440) | (@40)
Total amount of first coating layer 100 100 100 100 100 100 100 100 (% by weight)
EC content \ in first coating layer 0 8.0 16.0 32.0 48.0 64.0 72.0 80.0 (% by weight)
Second coating
Comparative Examples 4 to 6: Omega-3 fatty acid ester soft capsule with rosuvastatin coating
Rosuvastatin calcium salt, hydroxypropyl methylcellulose (HPMC 2910,
Shinetsu Co., Ltd., Japan), polyethylene glycol (PEG 6000, Sanyo Chemical
Industries, Ltd., Japan) and PVA (Kurary Co., Ltd., Japan) were added to a mixture of ethanol and water, and then mixed to obtain a coating solution.
The coating solution was coated onto the surface of the omega-3 fatty acid ester soft capsules obtained in Comparative Examples 1, 3 and Example 5, respectively, by using a coater (SFC-3, SEJONG Co., Ltd.), wherein the supply air temperature was 45°C and the product temperature was adjusted to 30°C. The products were dried for 30 minutes to remove residual solvent so that complex compositions were obtained. “Examples 8 to 12: Omega-3 fatty acid ester soft capsule with rosuvastatin coating
Rosuvastatin calcium, hydroxypropyl methylcellulose (HPMC 2910, Shinetsu
Co. Ltd., Japan), and polyethylene glycol (PEG 6000, Sanyo Chemical Industries,
Ltd., Japan) were added to a mixture of ethanol and water. Further, PVA (Kurary Co.
Ltd., Japan) or PVA-PEG graft copolymer (Kollicoat IR, BASF SE, Germany) was added thereto and then mixed to obtain a coating solution.
The coating solution was coated onto the surface of the omega-3 fatty acid ester soft capsule obtained in Example 5 by using a coater (SFC-3, SEJONG Co., 'Ltd.), wherein the supply air temperature was 45°C and the product temperature was adjusted to 30°C. The products were dried for 30 minutes to remove residual solvent so that complex compositions were obtained.
The compositions of second coating layers are summarized in Table 2.
Table 2
Comp. | Comp. | Comp.
Co Exd | Ex.5 | Ex.6 Ex.8 | Ex.9 Ex. 10 Ex. 11 Ex. 12
Soft capsule core Comp. | Comp. (with first coating) Ex 1 | Ex. 3 Ex.5 | Ex.5 | Ex.5 | Ex.5 | Ex.5 | Ex. 5 (mg) (mg) (mg) “Eo (mg)
Ethanol (mg) (644) | (644) | (644) | (644) | (644) | (644) | (460) | (460) yr 276) | 276) | (276) | (276) (460) | (460)
Total weight of 70 | 70 | 70 | 70 | 70 70 | 70 second coating layer (mg)
PVA or Kollicoat content i in second coating layer 62.9 | 62.9 0.0 25.7 | 40.0 | 629 | 77.1 | 77.1 (% by weight)
PVA/(HPMCPVA) 81.5 | 81.5 333 | 519 | 81.5 | 100.0 | 100.0 (% by weight) CLT
EVALUATION
Test 1: Disintegration test of soft capsules with barrier coating
A disintegration test was performed on the soft capsule prepared in
Comparative Example 1, the soft capsule with barrier coating prepared in
Comparative Example 3 and the soft capsules with hydrophobic coating prepared in
Examples 1 to 7, according to the method described in the general test method of the - Korean Pharmacopoeia. The results are shown in Figs. 1 and 2.
As shown in Figs. 1 and 2, the soft capsule prepared in Comparative Examples
1 and 3 showed satisfying results in disintegration time of less than 20 minutes according to the standards of the Korean Pharmacopoeia.
Satisfactory results were also obtained from the soft capsules prepared in
Examples 1 to 7. The soft capsule prepared in Example 7, however, showed a delay in disintegration time due to added hydrophobic excipient, i.e. ethyl cellulose, in an amount exceeded 75% by weigh for preventing a change in water content.
Therefore, it can be found that the preferable amount of the hydrophobic coating material in the first coating layer is 75% by weight or less, more preferably 72% by weight or less, based on the weight of the first coating layer, in order to satisfy the standards of the disintegration test.
Test 2: Water absorption rate of soft capsules with barrier coating
The capsules prepared in Comparative Examples 1 and 3, and Examples 1 to 7 were dried for 6 days at 30% RH, and the water content of gelatin capsule coating was measured. The water content change was observed by measuring weight loss on drying according to the method as described in the general test method of the Korean
Pharmacopoeia, wherein the measurement was taken at 90 °C in an equilibrium state, where weight of the sample no longer changes, and then the results were recorded as the initial water contents. | :
The samples were also tested for water penetration prevention effect by repeating the measuring method after 24 hrs exposure at 25 °C/60% RH and the results were recorded as the final water content, which are shown in Fig. 3.
As shown in Fig. 3, the soft capsules with no coating and conventional barrier coating as prepared in Comparative Example 1 and 3, respectively, showed a relatively great change in water content, i.e., 6% or more, as compared with the initial water content.
However, the soft capsules with hydrophobic coating containing ethyl cellulose prepared in Examples 1 to 7 resulted a slight change in water content. In particular, the soft capsules with hydrophobic coating containing ethyl cellulose in an amount of 16% or more, resulted only 3% change or less in water content, which shows the employment of ethyl cellulose significantly improves stability of the composition by reducing the water absorption by 50% or greater in comparison to coatings without ethyl cellulose. Further, it can be found that the preferable amount of the hydrophobic coating material used in the first coating layer is 15% to 75% by weight, more preferably 16% to 75% by weight, most preferably 16% to 72% by weight, based on the weight of the first coating layer.
Test 3: Dissolution rate of rosuvastatin
A dissolution test of rosuvastatin was performed on Crestor” (AstraZeneca plc,
UK) as a control drug, and the complex compositions prepared in Comparative
Examples 2, 4 to 6, and Examples 8 to 12.
The test was conducted, based on paddle method in the Korean Pharmacopoeia, at 50 rpm by using dissolution medium of 900 mL of 0.05 M citric acid buffer and the mediums were collected after 10 minutes, then their initial dissolution rates were measured. Also, the samples were stored in sealed HDPE bottles for six months under accelerated storage condition (40 °C/75% RH) and their dissolution rates were measured. The results are shown in Fig. 4.
As shown in Fig. 4, the complex composition prepared in Comparative :
Example 2 had poor dissolution rate of rosuvastatin from the initial measurement.
The complex compositions prepared in Comparative Examples 4 and 5 had decent initial dissolution rates of 80% or greater, but the rates deteriorated after six months of accelerated storage. Also, the complex composition prepared in Comparative
Example 6, which did not contain any PVA or PVA-PEG graft copolymer, had poor dissolution rate in comparison to the complex compositions of Examples 8 to 12.
On the other hand, the complex compositions prepared in Examples 8 to 12, wherein the first coating layer contains hydrophobic coating material, i.e., ethyl cellulose, in an amount of 16% to 72% by weight and the second coating layer contains PVA or PVA-PEG graft copolymer with rosuvastatin, had initial dissolution rates of 80% or greater. Also, the complex compositions exhibited little or no delayed release even after 6 months of accelerated storage, showing pharmaceutically stable dissolution rates. Accordingly, it can be found from the. results that the complex composition of the present invention has in vivo efficacy.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
Claims (9)
1. An oral complex composition, which comprises: (a) a soft capsule core comprising omega-3 fatty acid esters; (b) a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material; and (c) a second coating layer deposited on the first coating layer, which comprises: (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (11) polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or a mixture thereof.
2. The oral complex composition of claim 1, wherein the omega-3 fatty acid esters comprise ethyl esters of eicosapentaenoic acid and docosahexaenoic acid in an amount of 80% by weight or more. | :
3. The oral complex composition of claim 1, wherein the omega-3 fatty acid esters are present in an amount ranging from 100 mg to 2,000 mg.
4. The oral complex composition of claim 1, wherein the hydrophobic coating material is selected from the group consisting of cellulose acetate, polyvinyl acetate, ethyl cellulose, (meth)acrylic acid copolymers and a mixture thereof.
5. The oral complex composition of claim 1, wherein the hydrophobic coating material is present in an amount ranging from 15% to 75% by weight based on the total amount of the first coating layer.
6. The oral complex composition of claim 1, wherein rosuvastatin or the pharmaceutically acceptable salt thereof is present in an amount ranging from 1 mg to 50 mg.
7. The oral complex composition of claim 1, wherein polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or the mixture thereof is present in an amount ranging from 25% to 85% by weight based on the total amount of the second coating layer.
8. The oral complex composition of claim 1, which shows a rosuvastatin or its pharmaceutically acceptable salt releasing rate of 80% or more in 0.05 M citrate buffer within 10 min.
9. A method for preparing the oral complex composition of claim 1, which comprises the steps of: (1) preparing a soft capsule core comprising omega-3 fatty acid esters; (2) forming a first coating layer which encases the soft capsule core and comprises a hydrophobic coating material; and (3) forming a second coating layer on the first coating layer, which comprises: (i) rosuvastatin or a pharmaceutically acceptable salt thereof, and (i1) polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer or a mixture thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20110025940 | 2011-03-23 | ||
KR1020110041168A KR101310710B1 (en) | 2011-03-23 | 2011-04-29 | Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor |
PCT/KR2012/002134 WO2012128587A2 (en) | 2011-03-23 | 2012-03-23 | Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
SG193491A1 true SG193491A1 (en) | 2013-10-30 |
Family
ID=47280992
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SG2013069695A SG193491A1 (en) | 2011-03-23 | 2012-03-23 | Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor |
Country Status (31)
Country | Link |
---|---|
US (1) | US20140010872A1 (en) |
EP (1) | EP2688558B1 (en) |
JP (1) | JP2014508802A (en) |
KR (1) | KR101310710B1 (en) |
CN (1) | CN103442699B (en) |
AR (1) | AR085547A1 (en) |
AU (1) | AU2012231944B2 (en) |
BR (1) | BR112013023819A2 (en) |
CA (1) | CA2830342C (en) |
CL (1) | CL2013002611A1 (en) |
CO (1) | CO6801750A2 (en) |
CR (1) | CR20130491A (en) |
DO (1) | DOP2013000210A (en) |
EA (1) | EA023405B1 (en) |
EC (1) | ECSP13012959A (en) |
ES (1) | ES2550392T3 (en) |
GT (1) | GT201300217A (en) |
HK (1) | HK1189173A1 (en) |
IL (1) | IL228516A (en) |
JO (1) | JO3071B1 (en) |
MA (1) | MA35042B1 (en) |
MX (1) | MX343097B (en) |
MY (1) | MY157200A (en) |
NI (1) | NI201300086A (en) |
PE (1) | PE20140640A1 (en) |
SA (1) | SA112330374B1 (en) |
SG (1) | SG193491A1 (en) |
TW (1) | TWI571271B (en) |
UA (1) | UA106457C2 (en) |
WO (1) | WO2012128587A2 (en) |
ZA (1) | ZA201307871B (en) |
Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110236476A1 (en) | 2008-09-02 | 2011-09-29 | Amarin Corporation Plc. | Pharmaceutical composition comprising eicosapentaenoic acid and nicotinic acid and methods of using same |
NZ627238A (en) | 2009-04-29 | 2016-02-26 | Amarin Pharmaceuticals Ie Ltd | Stable pharmaceutical composition comprising ethyl eicosapentaenoate |
NZ624963A (en) | 2009-04-29 | 2016-07-29 | Amarin Pharmaceuticals Ie Ltd | Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same |
MY172372A (en) | 2009-06-15 | 2019-11-21 | Amarin Pharmaceuticals Ie Ltd | Compositions and methods for lowering triglycerides |
WO2011038122A1 (en) | 2009-09-23 | 2011-03-31 | Amarin Corporation Plc | Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same |
US11712429B2 (en) | 2010-11-29 | 2023-08-01 | Amarin Pharmaceuticals Ireland Limited | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
NZ744990A (en) | 2010-11-29 | 2019-10-25 | Amarin Pharmaceuticals Ie Ltd | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
US11291643B2 (en) | 2011-11-07 | 2022-04-05 | Amarin Pharmaceuticals Ireland Limited | Methods of treating hypertriglyceridemia |
US20130131170A1 (en) | 2011-11-07 | 2013-05-23 | Amarin Pharmaceuticals Ireland Limited | Methods of treating hypertriglyceridemia |
EP2800469B1 (en) | 2012-01-06 | 2021-08-25 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering levels of high-sensitivity (hs-crp) in a subject |
EP2866801A4 (en) | 2012-06-29 | 2016-02-10 | Amarin Pharmaceuticals Ie Ltd | Methods of reducing the risk of a cardiovascular event in a subject on statin therapy |
WO2014074552A2 (en) | 2012-11-06 | 2014-05-15 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides without raising ldl-c levels in a subject on concomitant statin therapy |
US20140187633A1 (en) | 2012-12-31 | 2014-07-03 | Amarin Pharmaceuticals Ireland Limited | Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis |
US9452151B2 (en) | 2013-02-06 | 2016-09-27 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing apolipoprotein C-III |
US9624492B2 (en) | 2013-02-13 | 2017-04-18 | Amarin Pharmaceuticals Ireland Limited | Compositions comprising eicosapentaenoic acid and mipomersen and methods of use thereof |
US9283201B2 (en) | 2013-03-14 | 2016-03-15 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for treating or preventing obesity in a subject in need thereof |
US20140271841A1 (en) * | 2013-03-15 | 2014-09-18 | Amarin Pharmaceuticals Ireland Limited | Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin |
GB2512098A (en) * | 2013-03-20 | 2014-09-24 | Roly Bufton | An oral dosage form |
KR102240429B1 (en) * | 2013-05-06 | 2021-04-15 | 한미약품 주식회사 | Composite formulation comprising a film coating layer containing rosuvastatin or a pharmaceutically acceptable salt thereof |
WO2014182003A1 (en) * | 2013-05-06 | 2014-11-13 | Hanmi Pharm. Co., Ltd. | Composite formulation comprising a film coating layer containing rosuvastatin or a pharmaceutically acceptable salt thereof |
US10966968B2 (en) | 2013-06-06 | 2021-04-06 | Amarin Pharmaceuticals Ireland Limited | Co-administration of rosiglitazone and eicosapentaenoic acid or a derivative thereof |
US20150065572A1 (en) | 2013-09-04 | 2015-03-05 | Amarin Pharmaceuticals Ireland Limited | Methods of treating or preventing prostate cancer |
US9585859B2 (en) | 2013-10-10 | 2017-03-07 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy |
US10561631B2 (en) | 2014-06-11 | 2020-02-18 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing RLP-C |
WO2015195662A1 (en) | 2014-06-16 | 2015-12-23 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense ldl or membrane polyunsaturated fatty acids |
WO2016003181A1 (en) * | 2014-06-30 | 2016-01-07 | 한미약품 주식회사 | Composite preparation comprising active ingredient-containing film coating layer |
WO2016003180A1 (en) * | 2014-06-30 | 2016-01-07 | 한미약품 주식회사 | Composite preparation comprising 5-α-reductase inhibitor-containing film coating layer, and method for producing the composite preparation |
CN106659690B (en) * | 2014-06-30 | 2020-08-18 | 韩美药品株式会社 | Composite preparation comprising a film coating containing an active ingredient |
TWI525110B (en) | 2014-12-24 | 2016-03-11 | 財團法人工業技術研究院 | Polymer, and pharmaceutical composition employing the same |
KR101950907B1 (en) * | 2016-02-05 | 2019-02-21 | 한국유나이티드제약 주식회사 | Oral preparation comprising liphophilic drug and a oilproof material coated solid formulation |
US10406130B2 (en) | 2016-03-15 | 2019-09-10 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids |
WO2017171484A1 (en) * | 2016-03-31 | 2017-10-05 | 한미약품 주식회사 | Composite preparation for oral administration containing omega-3 fatty acid or ester thereof, and hydroxymethyl glutaryl coenzyme a reductase inhibitor |
WO2018213663A1 (en) | 2017-05-19 | 2018-11-22 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides in a subject having reduced kidney function |
US11058661B2 (en) | 2018-03-02 | 2021-07-13 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L |
KR102296068B1 (en) | 2018-09-24 | 2021-09-02 | 애머린 파마슈티칼스 아일랜드 리미티드 | Methods of Reducing the Risk of a Cardiovascular Event in a Subject |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9509764D0 (en) * | 1995-05-15 | 1995-07-05 | Tillotts Pharma Ag | Treatment of inflammatory bowel disease using oral dosage forms of omega-3 polyunsaturated acids |
MXPA03004818A (en) * | 2000-11-29 | 2003-09-10 | Smithkline Beecham Corp | Composition containing statins and calcium for improved cardiovascular health. |
ITRM20040395A1 (en) * | 2004-08-03 | 2004-11-03 | Sigma Tau Ind Farmaceuti | COMPOSITION INCLUDING STATINES AND FATTY ACIDS OMEGA 3. |
ES2255426B1 (en) * | 2004-10-19 | 2007-08-16 | Gp Pharm, S.A. | PHARMACEUTICAL FORMULATION THAT INCLUDES MICROCAPSULES OF STATINS SUSPENDED IN ESTER ALKYLS OF POLYINSATURATED FATTY ACIDS (PUFA). |
US20070191467A1 (en) * | 2004-12-06 | 2007-08-16 | Reliant Pharmaceutical, Inc. | Statin and omega-3 fatty acids for lipid therapy |
MX2007006707A (en) * | 2004-12-06 | 2008-01-16 | Reliant Pharmaceuticals Inc | Omega-3 fatty acids and dyslipidemic agent for lipid therapy. |
CN101098690A (en) * | 2004-12-06 | 2008-01-02 | 瑞莱恩特医药品有限公司 | Omega-3 fatty acids and dyslipidemic agent for lipid therapy |
CN101208083A (en) * | 2005-03-08 | 2008-06-25 | 瑞莱恩特医药品有限公司 | Treatment with statin and Omega-3 fatty acids and a combination product thereof |
EA200800451A1 (en) * | 2005-07-28 | 2008-08-29 | Релайэнт Фармасьютикалз, Инк. | TREATMENT OF DIHYDROPYRIDINE BLOCKERS OF CALCIUM CHANNELS AND FATTY ACIDS OF OMEGA-3 AND THEIR COMBINED PRODUCT |
US8784886B2 (en) * | 2006-03-09 | 2014-07-22 | GlaxoSmithKline, LLC | Coating capsules with active pharmaceutical ingredients |
WO2007103557A2 (en) * | 2006-03-09 | 2007-09-13 | Reliant Pharmaceuticals, Inc. | Coating capsules with active pharmaceutical ingredients |
US20090041839A1 (en) * | 2007-05-23 | 2009-02-12 | Beasley Martin W | Pharmaceutical compositions for the treatment of pain |
JP5421126B2 (en) * | 2008-01-10 | 2014-02-19 | 武田薬品工業株式会社 | Capsule formulation |
WO2009101021A2 (en) * | 2008-02-13 | 2009-08-20 | Bayer Schering Pharma Aktiengesellschaft | Estradiol-containing drug delivery system |
KR20090091084A (en) * | 2008-02-22 | 2009-08-26 | 한올제약주식회사 | Controlled-release pharmaceutical formulation |
KR20090114190A (en) * | 2008-04-29 | 2009-11-03 | 한올제약주식회사 | Controlled release complex composition comprising hmg-coa reductase inhibitors and angiotensin-ii-receptor blockers |
ITFI20080243A1 (en) * | 2008-12-15 | 2010-06-16 | Valpharma Sa | FORMULATIONS FOR ORAL ADMINISTRATION OF OMEGA POLIENOIC FATTY ACIDS IN COMBINATION WITH NATURAL OR SEMI-SYNTHETIC STATINES. |
-
2011
- 2011-04-29 KR KR1020110041168A patent/KR101310710B1/en active IP Right Grant
-
2012
- 2012-03-21 JO JOP/2012/0059A patent/JO3071B1/en active
- 2012-03-22 TW TW101109888A patent/TWI571271B/en not_active IP Right Cessation
- 2012-03-23 MY MYPI2013003396A patent/MY157200A/en unknown
- 2012-03-23 JP JP2014501011A patent/JP2014508802A/en active Pending
- 2012-03-23 EA EA201391372A patent/EA023405B1/en not_active IP Right Cessation
- 2012-03-23 EP EP12760271.2A patent/EP2688558B1/en not_active Not-in-force
- 2012-03-23 MX MX2013010753A patent/MX343097B/en active IP Right Grant
- 2012-03-23 MA MA36333A patent/MA35042B1/en unknown
- 2012-03-23 AR ARP120100974A patent/AR085547A1/en unknown
- 2012-03-23 BR BR112013023819A patent/BR112013023819A2/en not_active IP Right Cessation
- 2012-03-23 PE PE2013002066A patent/PE20140640A1/en not_active Application Discontinuation
- 2012-03-23 CA CA2830342A patent/CA2830342C/en not_active Expired - Fee Related
- 2012-03-23 WO PCT/KR2012/002134 patent/WO2012128587A2/en active Application Filing
- 2012-03-23 CN CN201280014233.6A patent/CN103442699B/en not_active Expired - Fee Related
- 2012-03-23 ES ES12760271.2T patent/ES2550392T3/en active Active
- 2012-03-23 SG SG2013069695A patent/SG193491A1/en unknown
- 2012-03-23 US US14/006,191 patent/US20140010872A1/en not_active Abandoned
- 2012-03-23 UA UAA201312419A patent/UA106457C2/en unknown
- 2012-03-23 AU AU2012231944A patent/AU2012231944B2/en not_active Ceased
- 2012-03-24 SA SA112330374A patent/SA112330374B1/en unknown
-
2013
- 2013-09-11 CL CL2013002611A patent/CL2013002611A1/en unknown
- 2013-09-17 IL IL228516A patent/IL228516A/en active IP Right Grant
- 2013-09-19 GT GT201300217A patent/GT201300217A/en unknown
- 2013-09-20 DO DO2013000210A patent/DOP2013000210A/en unknown
- 2013-09-20 NI NI201300086A patent/NI201300086A/en unknown
- 2013-09-30 CR CR20130491A patent/CR20130491A/en unknown
- 2013-10-09 EC ECSP13012959 patent/ECSP13012959A/en unknown
- 2013-10-18 CO CO13247569A patent/CO6801750A2/en not_active Application Discontinuation
- 2013-10-22 ZA ZA2013/07871A patent/ZA201307871B/en unknown
-
2014
- 2014-03-09 HK HK14102333.6A patent/HK1189173A1/en not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2012231944B2 (en) | Oral complex composition comprising omega-3 fatty acid ester and HMG-CoA reductase inhibitor | |
US20240016803A1 (en) | Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin | |
JP5829607B2 (en) | Formulation of ω3 fatty acid | |
KR100870396B1 (en) | Oral administrative dosage form for treating cardiovascular system disease | |
EP2081550A2 (en) | Coating capsules with active pharmaceutical ingredients | |
JP6073352B2 (en) | Oral combined preparation comprising omega-3 fatty acid with improved stability and HMG-COA reductase inhibitor | |
RU2600804C2 (en) | Form of pharmaceutical composition multi-layer coating for oral administration containing omega-3 fatty acid or its alkyl ester, as well as medicinal agent based on statin | |
KR101830977B1 (en) | Oral complex formulation comprising omega-3 fatty acid or ester thereof and HMG-CoA reductase inhibitor | |
NZ616907B2 (en) | Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor | |
KR101954568B1 (en) | Oral complex formulation comprising omega-3 fatty acid or ester thereof and HMG-CoA reductase inhibitor | |
KR20130003501A (en) | Oral complex formulation comprising omega-3 fatty acid or ester thereof and hmg-coa reductase inhibitor | |
KR20170113396A (en) | ORAL COMPLEX FORMULATION COMPRISING OMEGA-3 FATTY ACID OR ESTER THEREOF, AND HMG-CoA REDUCTASE INHIBITOR |